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MOSCOW, July 1. /TASS/ An international group of scientists from the US, Canada, Germany, and Russia has revealed a substance produced in the human body that can regulate the functioning immune system cells, the macrophages, as reported by the press-service of the University of Informational Technologies, Mechanics, and Optics (ITMO).
It has been turned out that the substance called itaconate and released in large quantities by macrophages themselves, is very promising for the treatment of pathologies caused by excessive inflammation or oxidative stress due to its antioxidative and anti-inflammatory properties. For instance, it could be useful while treating cardiac, kidney, or hepatic ischemia, metabolic disorders and perhaps autoimmune diseases.
Russian scientists from the ITMO University together with colleagues from other countries have studied macrophages - the cells of immune systems responsible for the fighting pathogens. An important feature of macrophages is their ability to switch between different states depending on the concentration of various substances in the body. In total, there are three possible states: M0 – neutral, M1 – pro-inflammatory (mobilizing inflammatory response) and M2 anti-inflammatory (suppressing inflammatory response). M1 macrophages are the first who arrive to fight the infection. They provide an immune response but sometimes they become overly diligent which in turn can lead to the negative sequelae of the whole body. That is why the scientists are motivated to search for the tool of macrophages functioning regulation.
Itaconate breaks the substance flow in the macrophage cell by suppressing Sdh enzyme.ITMO press service
By unraveling the process of cell transition from inactive state to the anti-inflammatory one, the scientists have found that the activity of macrophages can be suppressed by the substance called itaconate," - reported in the press release. Herein, the itaconate is produced by macrophages when they switch from M0 inactive state to M1 pro-inflammatory state. “Itaconate sets the bar controlling M1 macrophage formation: if its concentration goes beyond a certain limit, macrophage activation falls,” says Alexey Sergushichev, one of the authors of the paper and Ph.D. student at ITMO University.
According to Sergushichev, without this substance, the inflammation would increase more than required. "In the future, with the help of itaconate, it will be possible to artificially manipulate the transition of macrophages from M0 to M1, meaning the possibility of restraining inflammations," - added the scientist.
To understand how itaconate reduces the activity of immune cells, the researchers examined the so-called Krebs cycle of macrophages, the manifold of biochemical reactions connected to the cellular respiration and related to the crossing of various metabolic pathways. It was disclosed that there exists two “bottlenecks” that can be influenced by itaconate. Exemplarily, it blocks the enzyme called Sdh (succinate dehydrogenase), which not only ensures the functioning of the tricarboxylic acid cycle but also links the cycle to signaling pathways to provide the exchange of information among macrophages. Thus, the blocking of Sdh slows down the activation of macrophages.
“Noteworthy, itaconate acts as an anti-oxidant and anti-inflammatory agent, simultaneously,” says Vicky Lampropoulou, the lead author of the paper and researcher at the laboratory of Maxim Artyomov at Washington University in St. Louis. “At the same time, itaconate is undangerous, as it is naturally produced by the organism itself. These features make it attractive for therapeutic applications for numerous diseases caused by excessive inflammation and oxidative influence.”
Now, the itaconate impact is on the test stage with the living organisms. The first experiments with mice have shown that the itaconate reduces damage after heart attack. However, according to the scientists, more work is needed to successfully apply the method to humans. The article summarizing the results of the study has been published in Cell Metabolism.